Cyclic AMP Response Element Modulator-alpha Suppresses PD-1 Expression and Promotes Effector CD4(+) T Cells in Psoriasis

Hofmann, S. R., Carlsson, E., Kapplusch, F., Carvalho, A. L., Liloglou, T., Schulze, F., Abraham, S., Northey, S., Russ, S., Surace, A. E. A., Yoshida, N., Tsokos, G. C., & Hedrich, C. M. (2021). Cyclic AMP Response Element Modulator-alpha Suppresses PD-1 Expression and Promotes Effector CD4(+) T Cells in Psoriasis. J Immunol, 207, 55-64.

Abstract

Effector CD4(+) T lymphocytes contribute to inflammation and tissue damage in psoriasis, but the underlying molecular mechanisms remain poorly understood. The transcription factor CREMalpha controls effector T cell function in people with systemic autoimmune diseases. The inhibitory surface coreceptor PD-1 plays a key role in the control of effector T cell function and its therapeutic inhibition in patients with cancer can cause psoriasis. In this study, we show that CD4(+) T cells from patients with psoriasis and psoriatic arthritis exhibit increased production of IL-17 but decreased expression of IL-2 and PD-1. In genetically modified mice and Jurkat T cells CREMalpha expression was linked to low PD-1 levels. We demonstrate that CREMalpha is recruited to the proximal promoter of PDCD1 in which it trans-represses gene expression and corecruits DNMT3a-mediating DNA methylation. As keratinocytes limit inflammation by PD-1 ligand expression and, in this study, reported reduced expression of PD-1 on CD4(+) T cells is linked to low IL-2 and high IL-17A production, our studies reveal a molecular pathway in T cells from people with psoriasis that can deserve clinical exploitation.
Last updated on 02/17/2024